TAK1 kinase is an indispensable intermediate in the intracellular signaling of innate immune responses. TAK1 is activated by many of distinct factors including Toll-like receptor ligands, intracellular microorganism sensor (NOD like receptor) ligands, IL-1 and TNF. TAK1 upregulates proinflammatory responses through activation of NF-B and mitogen activated protein kinase pathways. Thus, TAK1 is generally considered to be a positive regulator of inflammation. However, we have recently found that the targeted deletion of TAK1 in the epithelium of skin and intestine results in severe inflammation. These inflammatory conditions in the TAK1 mutant mice resemble chronic inflammatory diseases such as psoriasis in the skin and Crohn's disease in the intestine. We have found that TAK1 deletion causes accumulation of reactive oxygen species (ROS), and that inhibition of ROS can completely rescue cell death in cultured epithelial cells. Importantly, we found that treatment of the antioxidants in the epithelial-specific TAK1 deletion mice could prevent the epithelial cell death and diminishes inflammation. Therefore, we hypothesize that ablation of TAK1 signaling in epithelial cells causes dysregulation of ROS that is involved in epithelial cell death and inflammation. The objectives of this proposal are;1) to determine the mechanism by which ROS regulates epithelial cell death and inflammation;2) to identify the cause of ROS accumulation in TAK1-deficient epithelium. Outcomes from this project will delineate the relationship between ROS regulation and chronic inflammation, which could result in new approaches to regulate inflammation.